The capacity to undergo regression

The capacity to undergo regression
LR Ivs The capacity to undergo regression No MYCNamplification Near triploid nmber of chromosomes. No loss of chromosome 1p. {Ambros et al., 2000}

Residual after surgery
IR Residual after surgery The capacity to undergo maturation Persisting residual and maturing tumors in IR Neuroblastoma patients were not associated with tumor progression, despite MIBG uptake and/or elevated catecholamines {Marachelian et al., 2012}.

A superior prognosis for infants
< 18 vs >18 M A superior prognosis for infants Outcome of INSS Stage III Patients From the INRG Database Number 5-y EFS P-value 5-y OS Stage III 86 < 18 M 850 86% <0.0001 91% > 18 M 633 58% 66% Holly J. et al., Pediatic Blood Cancer 2014

The most common cancer in infants “<1 year old”
The most common extra-cranial solid cancer in childhood Accounts for about 7% of all cancers in children. The average age diagnosis “18 months”. 90% of cases are diagnosed by age 5. Very rare in people over the age of 10 years.

Site of primary tumor Local infiltration
Non- specific and mimic many childhood illnesses Primary sites Adrenal 40% Abdominal 25% Thoracic 20% Cervical 5% Pelvic 5% Site of primary tumor Local infiltration Sites of metastatic disease Metabolic disturbances

Site of primary tumor Horner ’ s syndrome Cough, dysphagia, breathlessness, thoracic inlet obstruction leading to superior vena caval syndrome. Abdominal pain, discomfort, fullness or rarely obstruction. Some tumors have intra - spinal and extra - spinal components (dumb - bell tumors) and it can lead to cord compression causing ﬂaccid paralysis and urinary and bowel disturbances. bladder or bowel obstruction.

Skull, orbits, jaw and long bones
Sites of metastatic disease Skin Orbit Liver bone marrow Brain Bone lymph nodes Skull, orbits, jaw and long bones

Opsoclonus-myoclonus-ataxia (OMA)
Associated with paraneoplastic mainfestation Opsoclonus-myoclonus-ataxia (OMA) It is a paraneoplastic syndrome occurs in 1-3 % of children with NB. It occurs at an average age of 19 months (6 to 36 months). OMA affects as few as 1 in 10,000,000 people per year. It is usually have favorable prognosis for survival as children tend to be: More mature, lower stage showing favorable histology and Absence of NMYC oncogene amplification.

Associated with paraneoplastic mainfestation Opsoclonus-myoclonus-ataxia (OMA) All children with OMA must be evaluated for Neuroblastoma→ as 50 % of children with OMA have an underlying Neuroblastoma. If the initial evaluation is unrevealing it should be repeated in several months. Autoimmune pathogensis have a role. The characteristic symptoms of OMA are rapid, dancing eye movements, rhythmic jerking (myoclonus) involving limbs or trunk, and/or ataxia. Neurologic symptoms precede tumor diagnosis in about half of these.

Associated with paraneoplastic mainfestation Opsoclonus-myoclonus-ataxia (OMA) Chemotherapy, corticosteroids, and IV immune globulin may improve long-term neurologic outcome. Symptoms refractory to these treatments may respond to Rituximab. However, children who have OMA are often left with long-term neurologic deficits (e.g., cognitive and motor delays, language deficits, and behavioral abnormalities).

Associated with paraneoplastic mainfestation Intractable diarrhea
Autonomous tumor secretion of vasoactive intesitinal peptide (VIP) that is associated with NB. VIP secretion can cause abdominal distension and intractable secretory diarrhea with hypokalemia. These symptoms usually resolve after removal of the tumor. The diagnosis is established by the presence of unexplained high-volume secretory diarrhea and a serum VIP concentration >75 pg/Ml. VIP-producing tumors are more often the less aggressive GNB and GN rather than undifferentiated neuroblastomas.

Spinal cord compression
MEDICAL COMPLICATIONS Intractable diarrhea Tumor lysis Hypertension Spinal cord compression OSA Patients with bulky or advanced stage disease may be classified as being at intermediate risk for tumor lysis syndrome and prophylaxis against the complications of tumor lysis syndrome may be considered . Cairo et al., 2010

MEDICAL COMPLICATIONS Spinal cord compression It is an oncologic emergency & occured in 7-15 % in patients. Neurologic recovery appears to be related to the severity of presenting neurologic deficits. Neurological manifestations of <4 weeks duration upon presentation are usually reversible (Fawzy et al., 2014). Spinal cord compression in NB can be effectively managed with upfront chemotherapy. Chemotherapy and laminectomy have equivalent overall survival outcomes.

MEDICAL COMPLICATIONS Spinal cord compression Initial surgical decompression should be reserved for benign variants only, including ganglioneuroma. RT is generally reserved for progressive symptoms despite chemotherapy. "In a review of 99 children with spinal cord involvement, 71 had residual impairments after a median follow-up of eight years. The most common impairments in this population were motor function, scoliosis, and bladder function {Simon et al., 2012}"

MEDICAL COMPLICATIONS
Hypertension Neuroblastoma tumor cells are characterized by defective catecholamine synthesis, which results in the accumulation and excretion of the intermediates homovanillic acid (HVA), VMA, and dopamine. Secretion of these catecholamines may give rise to symptoms.

Laboratory tests CBC, LDH LFT, KFT, electrolytes Urine HVA-VMA
ferritin NSE

a major tissue-binding protein.
ferritin a major tissue-binding protein. Raised ferritin results from direct secretion by the tumor. High levels of ferritin related to poor survival. The International Neuroblastoma Risk Group (INRG) recently analysed the prognostic markers in 1483 stage 3 neuroblastoma patients Holly et al.; 2014

NSE Enolases are glycolytic enzymes
2 - phosphoglycerate >>> >>> phosphoenolpyruvate. Three immunologically distinct subunits: alpha, beta, and gamma. Gamma enolase is found in neuron and called NSE. Non a speciﬁc marker increased levels Wilms tumor, Ewing sarcoma, Non- Hodgkin lymphoma, Acute leukemia, Non - malignant conditions, e.g. brain damage.

CT scan/MRI scan conﬁrms site, size, extension, vascular involvement.
Encasing major blood vessels is a characteristic feature of neuroblastoma. CT is the major imaging modality pre - surgery to demonstrate the relationship between tumor and blood vessels.

MRI scan is important to evaluate for intra - spinal extensions

MIBG scan is positive in about 90% patients and is an important single tool to identify all disease sites and to evaluate response sensitive and specific. Meta-iodobenzylguanidine (MIBG) that contains a small amount of radioactive iodine. MIBG is similar to nor epinephrine. The thyroid gland must be protected by the simultaneous administration of non-radioactive iodine (e.g., potassium iodide). Several hours or days later, the body is scanned with a special camera to look for areas that picked up the radioactivity. Can be used at higher doses to treat the NB.

Bone scan is only useful in MIBG negative neuroblastoma.
The role of the CT FDG - PET scan needs further evaluation and is a very promising imaging modality A retrospective analysis of paired MIBG and PET scans in 60 newly diagnosed neuroblastoma patients demonstrated that for International Neuroblastoma Staging System (INSS) stages 1 and 2 patients, PET was superior at determining the extent of primary disease and more sensitive for detection of residual masses. In contrast, for stage 4 disease, 123I-MIBG imaging was superior for the detection of bone marrow and bony metastases (sharp et al.; 2009).

Biopsies Diagnostic criteria Needle biopsy
Bone marrow aspiration and biopsy Diagnostic criteria An unequivocal histological diagnosis from tumor tissue by light microscopy, with or without immunohistochemistry, electron microscopy, or increased urine (or serum) catecholamine’s or their metabolites. Evidence of metastases to bone marrow on an aspirate or trephine biopsy with concomitant elevation of urinary or serum catecholamine’s or their metabolites {Brodeur et al., 1993}.

Hyperosmolar non ketotic coma
Hepatoblastoma Wilms A suprarenal location. Thoracic and retroperitoneal locations. Metastatic involvement of the bonemarrow. Spinal canal involvement. Skin nodules in newborns and infants. Other causes of Opsoclonus-myoclonus syndrome. Lymphoma Germ cell tumors soft tissue sarcoma Rhabdomyosarcoma Ewing sarcoma Lymphoma Dermoid cyst Congenital leukemia Infantile fibrosarcoma Infections Toxic exposures Hepatoblastoma Hyperosmolar non ketotic coma

St Jude ’ s proposed a surgico - pathological staging system.
Evans et al described the first staging system for neuroblastoma and used by the Children ’ s Cancer Group(CCG) in the USA. Involvement of lymph nodes and spread across the midline 1971 St Jude ’ s proposed a surgico - pathological staging system. Extent of surgery and lymph node involvement 1983 The TNM staging was proposed jointly by the American joint committee. Extent of surgery and lymph node involvement 1987

Post- surgical classification Assessment of lymph node involvement
International Neuroblastoma staging system (INSS) and International Neuroblastoma Response Criteria (INRC). Based on the assessment of resectability and surgical examination of lymph node involvement 1998 INSS modified Post- surgical classification Assessment of lymph node involvement 1993

Stage 1:(1X1) Localized tumor confined to the area of origin; complete gross excision, with or without microscopic residual disease. Representative ipsilateral and contralateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive). Stage 2a:(1X1) Localized tumor with incomplete gross excision; representative ipsilateral and non - adherent lymph nodes negative for tumor microscopically. Stage 2b:(2X2) Localized tumor with complete or incomplete gross excision; with ipsilateral non - adherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically. Stage 3:(3X3) Unresectable unilateral tumor infiltrating across the midline with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. Stage 4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defi ned in stage 4S). Stage 4S Localized primary tumor (as defined for stage 1, 2a or 2b) with dissemination limited to skin, liver and/or bone marrow ‡ (limited to infants less than one year old).

Description of International Neuroblastoma Response Criteria
Complete Remission (CR): No tumor, no metastases, normal markers. Very good Partial Remission (VGPR): Primary; reduction more than 90%, but less 100% Metastases; no tumor except bone {all preexisting lesions improved} Markers; decreased more than 90% Partial Remission (PR): Primary; reduction 50%-90% Metastases; no new lesions; 50%-90% reduction in measurable sites; BM samples positive; bone lesions the same as VGPR. Markers; decreased 50%-100% Mixed Response (MR):No new lesions; more than 50% reduction of any measurable lesion {primary or metastases} with less than 50% reduction in any other; less than 25% increase in any existing lesion. No Response (NR): No new lesions; less than 50% reduction but less than 25% increase in any existing lesion. Less than PR: No new lesions; less than 50% reduction Progressive Disease (PD): Any new lesion; increase of any measurable lesion by more than 25%; previous negative marrow positive for tumor.

M: Distant metastatic disease (except Stage MS).
INRGSS Pre- treatment clinical staging stystem It was designed for INRGCS 2009 L1: Localized tumor not involving vital structures as defined by the list of image defined risk factors and confined to one body compartment. L2 :Locoregional tumor with presence of one or more image defined risk factors. M: Distant metastatic disease (except Stage MS). MS :Metastatic disease in children younger than 18 months with metastases confined to skin, liver and/or bone marrow.

Image defined risk factors in neuroblastic tumors
Neck: • Tumor encasing carotid and/or vertebral artery and/or internal jugular vein • Tumor extending to base of skull • Tumor compressing the trachea Cervico - thoracic junction: • Tumor encasing brachial plexus roots • Tumor encasing subclavian vessels and/or vertebral and/or carotid artery Thorax: • Tumor encasing the aorta and/or major branches • Tumor compressing the trachea and/or principal bronchi • Lower mediastinal tumor, infi ltrating the costo - vertebral junction between T9 and T12 Thoraco - abdominal: • Tumor encasing the aorta and/or vena cava

Image defined risk factors in neuroblastic tumors
Abdomen/pelvis: • Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament • Tumor encasing branches of the superior mesenteric artery at the mesenteric root • Tumor encasing the origin of the coeliac axis, and/or of the superior mesenteric artery • Tumor invading one or both renal pedicles • Tumor encasing the aorta and/or vena cava • Tumor encasing the iliac vessels • Pelvic tumor crossing the sciatic notch Intraspinal tumor extension whatever the location provided that: • More than one third of the spinal canal in the axial plane is invaded and/or • the perimedullary leptomeningeal spaces are not visible and/or • the spinal cord signal is abnormal Infiltration of adjacent organs/structures: • Pericardium, diaphragm, kidney, liver, duodeno - pancreatic block, and mesentery

According to the balance between neural-type cells (primitive neuroblasts, maturing neuroblasts, and ganglion cells) and Schwann-type cells (Schwannian-blasts and mature Schwann cells) (NB), (GNB), and (GN). less than 5% cells Schwannian stroma rich Differentiating neuroblasts and mature ganglion cells Maturing GNB intermixed at least 5% cells Differentiating neuroblastoma

Neuroblasts at least 50% of the tumor mass
Undifferentiated neuroblastoma All cells Neuroblastoma Neuroblasts at least 50% of the tumor mass Poorly differentiated neuroblastoma less than 5% cells at least 5% cells Differentiating neuroblastoma

Ganglioneuroblastoma
Mature Schwannian stroma and ganglion cells Schwannian stroma -rich/ stroma –dominant /stroma poor Ganglioneuroblastoma >50% ganglioneuromatous, a minor neuroblastomatous GNB nodular Schwannian stroma rich GNB intermixed

Schwannian stroma dominant
Mature Schwannian stroma and ganglion cells Ganglioneuroma Schwannian stroma dominant Mature GNB nodular Differentiating neuroblasts and mature ganglion cells GNB intermixed Maturing

Shimada et al Age - linked classification Schwannian stroma - rich and stroma – poor FH and UH. 1984 The International Neuroblastoma Pathology Committee 1994 Ganglioneuroma (Schwannian stroma- dominant). Ganglioneuroblastoma, intermixed (Schwannian stroma- rich). Neuroblastoma (Schwannian stroma- poor). Ganglioneuroblastoma, nodular (Schwannian stroma- rich/ stroma- dominant and stroma- poor).

Degree of differentiation
Neuroblastoma Age >5 Years Undifferentiated High MKI Pathology GNB- intermixed, Ganglioneuroma Neuroblastoma GNB - nodular Age < 18 Months > 5 years Months Degree of differentiation Differentiating + low MKI Poorly differentiated and or intermediate MKI

Tumor cell ploidy MYCN amplification
A hyperdiploid 55% and 45% of are diploid. The prognostic significance: <18 months, Metastatic disease, MYCN NA Tumor cell ploidy MYCN amplification The oncogene MYCN is located on chromosome 2p at 2p 23 – 24. MYCN amplification is an intrinsic biological property. It is present at the time of initial diagnosis and this feature does not change with time.

Allelic loss of 1p occurs in about a third of neuroblastoma patients.
LOH of 1p was predictive of local recurrences in low stage disease. 1p deletion 11q loss 17q gain 25% of patients 11q aberrations are often not associated with MYCN amplification and are associated with reduced progression free survival. 11q strongly correlated with increase incidence of relapse particularly metastatic relapses. Having an extra part of chromosome 17 (17q gain) is also linked with a worse prognosis. This probably means that there is an oncogene in this part of chromosome 17, whereas whole chromosome 17 gain was associated with good Prognosis {Van Roy et al., 2009}.

Anaplastic lymphoma kinase ( ALK )
A predisposition gene for familial neuroblastoma. It can be used as target therapy.

COG uses age, MYCN status, stage, histology, and DNA ploidy.
SIOPEN uses age, MYCNstatus, and surgical risk factors defined by imaging for assigning risk - group for locoregional tumors. Prognostic factors • Stage. • Age ( < 18 months versus ≥ 18 months (547 days)). • Histological category (ganglioneuroma, ganglioneuroblastoma– intermixed). • Grade of tumor differentiation (differentiating versus undifferentiated or poorly differentiated). • MYCN status. • Presence/absence of 11q aberration. • Ploidy ( ≤ 1.0 versus > 1.0).

Risk INSS Stage Age MYCN Status INPC Classification DNA Ploidy Low 1 Any 2A/2Bc Non amplified High 2A/2B Amplified Intermediate 3 <547 d ≥547 d Favorable Unfavorable 4 <365 d ≥365- <547 d =1 >1 ≥547d 4S

Stage I---- LR NMYC A----HR II III IV < 18 Months > 18 Months FH
IR HR III IV HR IR HR Age IR < 18 Months > 18 Months Histology IR HR FH UH

Stage I---- LR NMYC A----HR II III IV >18 Months 12-18 Months
IR HR III IV HR IR HR Age HR >18 Months IR 12-18 Months < 12 Months Histology+ DNA I IR HR FH+DNA I>1 UH or DNA I=1

Stage IV S HR LR IR NMYC A FH + DNA I >1 UH or DNA I<1

Principles of therapy Risk adapted therapy Recurrent neuroblastoma

Different treatment modalities like surgery, chemotherapy and radiation therapy.
Role of surgery It can be used both in diagnosis and treatment. The primary treatment for low-risk tumors. Resectability is determined by tumor location and mobility, relationship to major nerves and blood vessels, the presence of distant metastases, and patient age.

Role of surgery For children with localized disease, without MYCN amplification, gross surgical excision is considered the main requirement for cure. {De Bernardi et al., 2008} Localized but unresectable NB carries a poorer prognosis except in Infants or {Rubie et al., 2011} Children with favorable biological features. {Cohn et al., 2009}

Chemotherapy: Indications: neoadjuvant or adjuvant
Low-risk disease: multi-agent low or moderate intensity chemotherapy is reserved for those whose Tumors cannot be resected Who have threatening symptoms of spinal cord compression or respiratory or bowel compromise. Intermediate-risk disease: Moderately intensive multi agents chemotherapy is applied before attempted resection. High-risk disease: intensive chemotherapy with a combination of agents is used to shrink primary and metastatic tumors.

Radiation therapy: Indications LR NB patients: It is reserved for unresectable tumors or Progressive tumors unresponsive to chemotherapy or Life threatening complications, neurologic compromise, or tumor-related organ dysfunction unresponsive to emergency chemotherapy. Intermediate-risk: Currently, cooperative groups withhold RT for patients with, and recommend it only in the setting of disease progression despite surgery and chemotherapy {Brodeur et al., 2011} High risk:

Low Risk NB: Observation Surgery Chemotherapy Radiation therapy
Some newborns with small adrenal masses. Some infants with localized NB. Asymptomatic stage 4S disease {Nuchtern et al., 2012} Surgery alone is the primary treatment for low-risk tumors {De Bernardi et al., 2008} It should be delayed when <50 % of the tumor can be safely removed and neoadjuvant chemotherapy should be administered prior to surgery. low or moderate intensity Those whose tumors cannot be resected Who have threatening symptoms of spinal cord compression or respiratory or bowel compromise. Unresectable tumors or Progressive tumors unresponsive to chemotherapy or For those with life threatening complications, neurologic compromise, or tumor-related organ dysfunction unresponsive to emergency chemotherapy.

IntermediateRiskNB: SURGERY Chemotherapy Radiation therapy It is recommend it only in the setting of disease progression despite surgery and chemotherapy {Brodeur et al., 2011}. Moderately intensive multi agents chemotherapy In a COG trial for intermediate risk NB, Four cycles of chemotherapy were given for tumors with favorable biologic features Eight cycles were given for tumors with unfavorable features The ultimate extent of surgical resection necessary for optimal outcomes has not yet been determined {Baker et al., 2010}

High Risk NB: 1.Induction 2.Local Control Intensive chemotherapy with a combination of agents (e.g., platinum agents, cyclophosphamide, doxorubicin, etoposide) is used to shrink primary and metastatic tumors. Local control of the primary tumor is achieved with surgical resection and radiation therapy. The importance of achieving a gross total resection of the primary tumor in patients with disseminated disease is controversial, with some studies {Zwaveling et al., 2012}, But not others suggesting a better outcome for complete resection {Simon et al., 2013}. Radiotherapy dosed to the primary tumor bed and other sites of bulky disease may be beneficial in preventing local tumor recurrence {Haas-Kogan., 2003}

High RiskNB: 3.Consolidation 4.Maintenance The consolidation phase includes higher dose chemotherapy {melphalan and busulfan} followed by autologous hematopoietic stem cell rescue {Laprie et al., 2004}. Aim: eradication of minimal residual disease. The backbone: 13-cis-retinoic acid (RA) . Retinoids ---are substances that are similar to vitamin A. Benefit to help some cells mature into normal cells. A COG study it improved their survival and lowered their risk of recurrence. Time---after completion of consolidation therapy to HR NB patients.

High RiskNB: 5.Novel therapies
Additional immunotherapy: anti-GD2 antibodies was also found to have benefit over (RA) alone for prevention of recurrence in a randomized trial {Yu AL et al., 2010}. The immunotherapy approach resulted in a statistically significant improvement in the two-year EF and OS rates (66 versus 46 %, and 86 versus 75 %, respectively). Immunotherapies: anti-GD2 antibodies {Shusterman et al., 2010} Targeted autologous T-cells {Louis et al.; 2011} Neuroblastoma vaccines. Targeted therapy with drugs that act through known genetic mutations (e.g., ALK) or induce apoptosis (e.g., fenretinide). {La Madrid et al., 2012} Modifiers of the tumor microenvironment such as antiangiogenic agents or bisphosphonates {Russell et al., 2011} Iodine-131-metaiodobenzylguanidine (MIBG), in conjunction with autologous peripheral blood stem cell rescue {Matthay et al., 2007}

Tumor growth due to maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology. Patients may have persistent maturing disease with (MIBG) uptake that does not affect outcome, particularly in patients with LR and IR disease {Marachelian et al., 2012}. When NB recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy {London et al.; 2011}.

Time from diagnosis to first relapse.
Prognostic factors determined at diagnosis for post relapse survival include the following {London et al., 2011}: Age. INSS stage. MYCN status. Time from diagnosis to first relapse. LDH level, ploidy, and histologic grade of tumor differentiation (to a lesser extent). Among those older than 18 months, differentiating tumors did much better than undifferentiated and poorly differentiated tumors. Stages 1 and 2 have a better prognosis than stages 3 and 4 Hyperdiploidy had a better prognosis than patients with diploidy

Low Risk Locoregional Surgery if not for chemotherapy Surgery
unfavorable biology favorable biology Age < 1 Y >1 Y <90% >90% >90% <90% Aggressive combination chemotherapy Chemotherapy Observation Chemotherapy Observation

Aggressive combination chemotherapy
Low Risk Metastatic Age >1 Y < 1 Y Aggressive combination chemotherapy completely favorable, 4S pattern, the recurrence or progression is within 3 months of diagnosis. Not 4S pattern or the recurrence or progression is >3 months of diagnosis. Observation Chemotherapy

like patients with newly diagnosed HR NB
Intermediate Risk Locoregional > 3 M Metastatic Surgery like patients with newly diagnosed HR NB >90% <90% Observation Chemotherapy

HighRisk Any recurrence in patients initially classified as high risk signifies a very poor prognosis {London et al., 2011}. Clinical trials may be considered. Palliative care should be considered as part of the patient's treatment plan.

HighRisk 1.Chemotherapy Topotecan in combination with cyclophosphamide or etoposide {London et al., 2010} [Level of evidence: 1A]. Temozolomide with irinotecan {Bagatell et al., 2011} [Level of evidence: 2A]. High-dose carboplatin, irinotecan, and/or temozolomide has been used in patients resistant or refractory to regimens containing topotecan {Kushner et al., 2010}.

HighRisk 2.Iodine 131-MIBG (131I-mIBG) For children with recurrent or refractory NB, 131I-mIBG is an effective palliative agent and may be considered alone or in combination with chemotherapy (with stem cell rescue) in a clinical research trial {French et al., 2013} [Level of evidence: 3iiiA].

3.Second autologous stem cell transplantation (SCT)
HighRisk 3.Second autologous stem cell transplantation (SCT) In the setting of a clinical trial. German high-risk NB trials described 253 children relapsing after intensive chemotherapy with autologous SCT who had a 5-year OS rate of less than 10%. Only 23 of the 253 patients eventually proceeded to a second autologous SCT following retrieval chemotherapy {Simon et al., 2011} [Level of evidence: 3iiiA]. Among these patients, the 3-year OS rate was 43%, but the 5-year OS rate was less than 20%. Only a small minority of relapsed high-risk NB patients may benefit. For children with recurrent or refractory NB, 131I-mIBG is an effective palliative agent and may be considered alone or in combination with chemotherapy (with stem cell rescue) in a clinical research trial {French et al., 2013} [Level of evidence: 3iiiA].

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